Molecular Mechanisms of Dopaminergic Neuronal Protection by Regulation of Proteasome Activity

包括帕金森氏病在内的神经退行性疾病具有共同的特征，即选择性神经元死亡和神经元中不溶性蛋白质的积累。在帕金森病中，这两个特征是选择性多巴胺能神经元死亡和α -突触核蛋白阳性路易小体的出现。在之前的Grant-in-Aid for Scientific research（14570591）的研究中，我们报道了蛋白酶体抑制导致α -突触核蛋白阳性包体，相反，它阻止多巴胺能神经元死亡（Sawada et al.， J.Biol.Chem.279:10710,2004）。本研究采用半帕金森动物模型，研究了6-羟基多巴胺（6-OHDA）对体内多巴胺能神经元退行性变的抑制作用。组织学分析显示，蛋白酶体抑制抑制了该模型中的多巴胺能神经元变性，行为学分析显示，蛋白酶体抑制可阻断半帕金森病（Inden et al., j.p arpharmacol . sci .97:203-211,2005）。这些结果似乎是矛盾的，因为先前的假设认为不溶性蛋白质的积累可能导致多巴胺能神经元变性。在本研究中，我们研究了蛋白酶体抑制神经保护的分子机制，发现蛋白酶体抑制可升高热休克蛋白70 （hsp70）和谷胱甘肽（提交和修订）。此外，我们报道了6-OHDA引起的多巴胺能神经元死亡是由对醌、有毒多巴胺中间体介导的（Izumi等）。J.Neurosci.Res。79:849, 2005;王晓明，王晓明，王晓明，等。神经科学进展。2005)。此外，我们报道了该疾病患者乳头状括约肌的去甲肾上腺素神经末梢受到干扰（Sawada et al., JAMA 293:932-924,2005）。

Neurodegenerative disorders including Parkinson disease have common features, selective neuronal death and accumulation of insoluble proteins in the neurons. In Parkinson disease these two features are selective dopaminergic neuronal death and the appearance of alpha-synuclein positive Lewy bodies. In the previous research of Grant-in-Aid for Scientific Research (14570591), we reported that proteasome inhibition causes alpha-synuclein-positive inclusions, and on the contrary, it blocks dopaminergic neuronal death (Sawada et al., J.Biol.Chem.279:10710,2004). In this research we investigated the effect of proteasome inhibition on dopaminergic neuronal degeneration in vivo using animal hemi-Parkinson model by 6-hydroxy dopamine (6-OHDA). Histological analysis revealed that proteasome inhibition blocks dopaminergic neuronal degeneration in this model, and behavioral analysis showed that hemi-Parkinsonism is blocked by proteasome inhibition (Inden et al., J.Pharmacol.Sci.97:203-211,2005). These results seem paradoxical because previous hypothesis suggest that accumulation of insoluble proteins could cause dopaminergic neuronal degeneration.In this research we investigated the molecular mechanisms of neuroprotection by proteasome inhibition and found that proteasome inhibition elevated heat shock protein 70 (HSP7O) and glutathione (submitted and revised). In addition we reported that dopaminergic neuronal death by 6-OHDA is mediated by p-quinone, toxic dopamine intermediates (Izumi et al. J.Neurosci.Res. 79:849,2005;Izumi et al., J.Neurosci.Res.82:126-137,2005). Furthermore, we reported that sympathetic norepinephrine neuronal terminals in the papillary sphincter muscles are disturbed in patients in the disease (Sawada et al., JAMA 293:932-924,2005).